Arsenic sulfathiazole chelate complex



Patented May 16, 1956 UNITED STATES PATENT OFFICE ARSENIC SULFATHIALZOLECHEL COMPLEX IbertMellan, Chicago, IlL, assignor to Chicago PharmacalCompany, Chicago, .1114, as vcorporate.

tion of Illinois No Drawing. Application Janua 5,; 5.." Serial No.57259. I

.0 m It The invention relatesato improvements in msdicinal compounds andmethods of preparingihe same and has for itsjpitimary object theproduction oinew and novel, medicinal compounds or coinplexswhicli arehighly efficient in use.

Another, object of the invention, is; to provide new, i and novel.compounds or complexes of the salts of inorganic kmentssuchassilyer,copper, arsenic, bismuth, mercury, gold" or antimony,

combined with one or.) more of the sulfa drugs,v

. new andnovel methodsof v procedure for; producing such compounds orcomplexes.

Other objects will appear" hereinafter.

The invention consists'of the compounds or complexes and the methods of;procedure ihereinafter described andrclaimed.

Example I In preparing, the .silver-su1fathiazolecomplex,

a,.1,0 normal solution"ofrsulfathiaaole; is obtained by, adding 255.31gramsoi sulfathiazolei and43 grams of sodium; hydroxide to 80 0; cc. ofwater. When all the sulfathiazole has dissolved, the

solution is diluted tolOOO co. and filtered. The. v 1 natureofzsolution, its concentration and the -.hy-

drogen ion concentration heforev and aiter; the reaction play;an,important ,rolein the character ofithelresulting complex formed.Therefore; the type of complex desired will determine'the conditionofmanufacture. A solutionofsilver nitrate is obtainednby dissolving, 1619.9; ramsaof silver:nitratesinenouglr distilledwwater to-make1000.'cc.' 500 vcc. of thesuliathiazole so11 1 tion-,is thendi1utedto:500;0 ,cc.,/ and ;to.this is added, with constant stirring,,500 cc;.of;the:silvernitrate isolution afterithelatter has been dilutedto 590,0cc.

Immediately, at colloidal precipitate .;is, formed which darkens coloron standing, butsuch darkening in color may; bBnOVBICOIIlQ by; adding Za little .ammonialwater; The originalr-suliathiazole solution has a-pI-I' of' 1-1.4; .the silver nitrate solution a pH- of 6.7 and; theresultingzmixtune has a-pH'of '65: The-chemical iormulaiionchelate ringof the complex thus-xproduced-may be expressed as follows:

a le oi; the-ssul a hi zq i q utiomm used so that; the resultingreaction mixture is ico loi all; milk complexsis ipneventedaandcipitatea is ffOLIIlQd-u wh ch ma ramme washed,vconcentratedgandmsedyasa pastewor as .a 1d ysnow erifor-v:ma treatm nt:-o mingw rm mfections,such as athletes foot, with good results.

Example 2 In preparing the silver sulfanilamide complex, a solution ofsulfanilamide is obtained by adding 172.14 grams oi,sulfanilamide andJAOgrams of sodium hydroxide to 800 cc. of distilled water. Ordinarily, aclear solution will result, but a small, additional amountofsodiumhydroxide may have to be added to dissolve the sulfanilamide completely.The resulting solution is diluted to 1000 cc. and filtered. 10 litersioiithe aqueous solution containing 2500 cc. 0f, 1'.0. Nsulfanilamidesodium is added, with constantstirring, .to 10j1iter oj an aque us ol onma as-250 mmoil-answe trate A i e o lo al-, r mit e ilire u in mi iatur-h la PIT Q 1 nd ma beremovedswashed nd onc tr t dnss s d ei The tratedas before. 1 complex is to mix 10 liters of an aqueous solutioncontaining 5000 cc. of 1.0 N sulfadiazine sodium with 10 liters of anaqueous solution, containing} 3 chemical formula or chelate ring of thecomplex thus produced may be expressed as follows:

no H Ag O= NH Example 3 In preparing the silver-sulfapyridine complex, asolution of sulfapyridine is obtained by adding 289.18 grams ofsulfapyridine sodium,

to enough water to make 1000 cc. and then filtering the same. 10 litersof an aqueous solution containing 2500 cc. of 1.0 silver nitratesolution added, with constant stirring, to 10 liters of an aqueoussolution containing 2500 cc. of 1.0 N sulfapyridine sodium produces agelatinous precipitate which transforms the reaction mixture into pastynearly solid mass, the mixture having -a pH of 8.9, and may be removed,washed and concentrated as before. The chemical formula .or chelate ringof the complex thus produced may be expressed as follows:

Example 4 2500 cc. of 1.0 N silver nitrate. This mixture has "a pH of7.7. The chemical formula or chelate ring complex thus produced may beexpressed as follows Example 5 complex are formed. The chemical formulaor chelate ring of the complex thus produced may be expressed asfollows:

0 Ag NH: 0=l N 6H Solutions containing the corresponding compounds ofthe metals mentioned, may be prepared as follows:

Example 6 Copper sulfate solution.A 1.0 molar copper sulfate solution isprepared by adding 249.71 grams of CuSO4.5I-I2O to enough water to make1000 cc. Then filtered.

Example 7 Mercurz'c chloride solution.--A 0.5 normal mercuric chloridesolution is prepared by dissolving 135.8 grams of mercuric chloride inenough water to make 2000 cc. When all of the salt dissolves filter.

Example 8 Bismuth chloride solution.A 0.5 molar solution is prepared bydissolving 259.5 grams of basic bismuth carbonate ((BiO)2COa. H2O) in425 cc. of concentrated hydrochloric acid and diluting to 1000 cc. withwater.

Example 9 Arsenic trichloride solution.A 1.0 N arsenic trlchloridesolution is prepared by dissolving with the aid of heat, 66 grams ofarsenic trioxide U. S. P. X1 in 400 cc. of concentrated hydrochloricacid and suilicient water to make 1000 cc.

Example 10 Gold tribromide solution.-A 1.0 N gold tribromide solution isprepared by dissolving 145.65 grams of gold tribromide in suflicientwater to make 1000 cc. The addition of hydrochloric acid may be neededto aid in getting the salt in solution.

Example 11 Antimony solution.A 1.0 N solution is prepared by dissolving111.3 grams of antimony and potassium tartrate in sufiicient water toyield a volume of 1000 cc.

From these, by replacing the silver atom in the foregoing formulae withthe elements, Cu/z, Bi/a, Hg/z, As/s, Au/a. Sb/s, the various othercomplexes may be formed as follows:

Example 12 Copper sulfanilamide complea:.This complex is made by mixing1500 cc. of an aqueous solution containing 500 cc. of a 1.0 Nsulfanilamide sodium with 1500 cc. of an aqueous solution containing 250cc. 1.0 molar copper sulfate. A thick gelatinous green precipitate isformed which turns blue-green in color. The color varies with the methodof making and the pH of the resulting mixture. In this bath theresulting mixture has a pH of 9.7. The quantities of each solution canbe so varied as to use up all of the sulfanilamide and the coppersulfate or to have an excess of either the sulfanilamide or the coppersulfate. A light green colored complex of copper sulfanilamide is madeby mixing 1500 cc. of an aqueous solution containing 500 cc. 1.0N-'sulfanilamide' with=l500 cc. of an aqueous solution containing-- Theresulting 500 cc. 1.0 molar copper sulfate. mixture has a pH of 4.7.

Ea'ample13 Copper salfapym'dine complex.500 cc. of. 1.0

sulfapyridine sodium diluted to 1000.00. isadded 110-1000 cc. of anaqueous solution containing250.

cc. of 1.0. molar copper sulfate. Alightv green precipitate is. formedwhich turns olive-greenand,

finally purple incolor. The mixture. has a pH 01-7.4;

Example 14 Copper sulfadiazine compleax-One. liter of solutioncontaining 500Tcc. .1.0 N sulfadiazine is mixed with one liter ofsolution containing 250 cce 1.0: m01ar' copper sulfate. A light greenprecipitateis formed which changes'toa dark green andfinally to a purplecolored precipitate. The resulting-mixture before filtrate andpurification hasa pH 8.4.

Example 15 Copper sulfathiaeole comple:c.-One liter of solutioncontaining. 500 cc. of 1.0 N. sulfathiazole sodium isadded to 1000 cc.of a solution containing-250 cc. 1.0 molar copper sulfate. A thickgelatinous precipitate is formed which goes thru a change offieetingcolors and finally turns purple.

Whenthe reactionis completethe pH is 5.6.

Example 16.

Copper sulfaguanidine compZer.-192' grams of sulfaguanidine aredissolved. in 1000 cc. of hot water. and to this is added 500 cc. of 1.0molar copper..sulfate.. Thesolution turns green in colorand-.aprecipitate beginsto form, so 200 cc. of concentrated hydrochloricacid is added. Upon standing'crystals of coppersulfaguanidine begintoLform.

Example 17 Mercurysulfathiazole comple:c.-Two liters of;

solution containing 500 cc. of 1.0 Nsulfathiazolez sodium-are mixed.with two liters of. solution .containing 1000..cc; of- 0.5 mercuricchloride. white thick precipitate isformed and the mixture has a pH of6.5.

Example 18 'M'erc'ury :sulfadz'azine comple:r.-One liter" of.ani'aqueousv solution containing 500 cc. of 1.0 N

sulfadiazine: sodium is mixed with 2000.00. of an aqueous solutioncontaining 1000 .cc; of 0.5 N mercuric chloride. A White precipitateiisformed andjthemixture has a pH of 9.4. Another. way of making thiscomplex is. tomix 100000. of 0.5 N sulfadiazine sodium with 2000 cc. of0.5 N mercuric .1chloride. formed. The resulting mixture has a pH of7.8.

Example 19 Mercury sulfapyricline complem.500 cc. of 1.0

A thick White precipitate is N :sulfapyridine sodium diluted to a literis added.

to 2000 cc. of 0.5. N'mercuric chloride solution.

A thick white gelatinous precipitate iszformed. Th'emixture has a pH6.4:.

Erample 20 Mercury sulfam'lamicle complex-500 cc. of

1.0:N'sulfanilamide sodium diluted-to a liter is added, with constantstirring, to 2000. cc. of 0.5;

N mercuricv chloride. A white precipitate is formed and after thereaction is complete the mixture has a pH "of 6.7.

Ea'c ample 21 Bismuth sulfathiazole cOmpZexF To 500 cc: of

Upon cooling the solution crystals of the complex begin to form.

Example 22 Bismuth"salfaguanidine complex.-500- "cc? of 0:5'molarbismuth chloride -are used to dissolve" grams ofsuIfag-uanidine.At times it is *n'e essary to use --heat-andtheaddition'of a 'little'concentrated hydrochloric acid (60 cc.). cooling the complex is formed.

Example :23

Upon

Bismuth sulfaguam'cl'ine completc;'-To cc'xof- 0.5 molar bismuthchloride isadded 192* grams of sulfaguanidine- The 'mixture is heatedand 200 cc. of hydrochloric acid added. The addition of'acid and theapplication of heatre'sults.

in'a clearsolution; Upon"coolingithe"solution" crystals of bismuthsulfaguanidine complex'are formed."

EZ'cample"24"' Bismuth sulfadz'azz'ne complem.This complex is. formed:by; adding .500 cc.- of. 0.5 molar bismuth chloride; solution to. .1750; cc; of 11.0. N t sulfadiazine sodium. A...thick.-precipitateisformed which -is dissolved. by .the. addition of 200-cc. concentrated ahydrochloric .acid andi heat. Upon .standing and cooling yellow crystalsare formed. Theseare removed and are purifiedabyleither working orrecrystallization. Another method of preparing this complex istodissolve "grams ofsulfadiazine in 500cc. of 015 molarbismuthchloride;'T6 1 aid solution it may be necessary to apply heat" and to add'mo'rehydrochloric acid (60 c'c'.) Up: on. standing or by cooling. yellowcrystals of bismuth 'sulfadia'zine are formed.

Bismuth sulfapyrzdz'ne: complex-To 500 cc. of 0.5 molarbismuth chlorideis added 750 cc. of 1.0 N' sulfa'pyridlne sodium solution. A'precipitateis formed which' is dissolved by heatlrig' andiaddin'g 100cc. ofhydrochloric acid. Upon 7 standing or cooling translucent crystals areformed which could -be-purified by recrystallization, Anotherv way. .toprepare thiscomplex is to dissolve. 186.9 grams of sulfapyridine in50000. of e 0.5 molar bismuth chloride solution. At times it'- may benecessary to apply-heat to aid inthe solution or it may require theaddition of hydro chloric acid. Upon standing a crystalline complex isformed.

Emample26 Bismuth sulfamlamide comp'letc;"To 500 cc." of 0.5m'ol'arbismuth 'Chlbri'dEISOlutiOil "is added 129 grams of sulfanilainide;Toaid solution heat is applied and 30 cc. ofr hyd rochloric acid isadded. Upon dilution with water, the bismuth sulfanil'amide complexseparatesou't and is re- 75 moved and" washe'dby "filtration? Example 27Arsenic sulfathiazole complex.To make this complex add 255 grams ofsulfathiazole to 1000 cc. of 1.0 N arsenic chloride solution and stir.In a few minutes the whole mass solidifies. The solid complex is thenbroken up and washed. Another method of making this complex is to add2000 cc. of boiling water to a liter of 1.0 N arsenic chloride and thendissolve in this solution 255 grams of sulfathiazole. Upon standing anarsenic sulfathiazole complex crystallizes out of solution. In place ofthe two liters of boiling water we can use one liter of water containing50 cc. of concentrated hydrochloric acid.

Example 28 Arsenic sulfaguanidine complex.This complex is formed byadding 232 grams of sulfaguanidine to 1000 cc. of 1.0 N arsenic chloridesolution. The mixture is heated to aid in the solution ofsulfaguanidine. Upon standing the complex crystallizes out of solution.

Example 29 Arsenic sulfadiazine complex.250 grams of sulfadiazine isdissolved in 1000 cc. of 1.0 N arsenic chloride solution with the aid ofheat. Upon standing or cooling the complex is formed.

Example 30 Arsenic sulfapyridine complex.2492 grams of sulfapyridine aredissolved in 1000 cc. of 1.0 N arsenic chloride solution with or withoutthe aid of heat. Upon standing and cooling the complex crystallizes outof solution.

Example 31 Arsenic sulfanilamide complex.To form this complex dissolve172 grams of sulfanilamide in 1000 cc. of arsenic chloride solution withor without the aid of heat. Upon cooling the complex of arsenicsulianilamide will crystallize out of solution.

Example 32 Gold sulfathiazole complex.This complex is formed by adding102 grams of sulfathiazole to 400 cc. of 1.0 N gold chloride. When allof the sulfathiazole dissolves, a red precipitate begins to form. Theformation of this red complex is hastened when the solution is heated.The complex can be purified by dissolving it in a dilute solution ofhydrochloric acid and recrystallizing.

Example 33 Gold sulfaguanidine complex.92 grams of sulfaguanidine aredissolved in 400 cc. of 1.0 N gold chloride solution and 100 cc. ofwater. A light brown colored complex is formed upon standing.

Example 34 Gold sulfanilamide complex-69 grams of sulfanilamide aredissolved in 400 cc. of 1.0 N gold chloride and 100 cc. of water. In onehour or so a brown to red colored complex of gold sulfanilamide isformed.

Example 35 Gold suljadiazine complex.lco grams of sulfadiazine aredissolved in 400 cc. of 1.0 N gold chloride and 100 cc. of water. Uponstanding a red colored complex is formed.

Example 36 Gold sulfapyridine complex.lOO grams of suliapyridine aredissolved in 400 cc. of 1.0 N gold 8. chloride and 300 cc. of 10%hydrochloric acid. Upon standing or cooling a red colored complex isformed.

Example 37 Antimony sulfathiazole complex.This complex is formed bymixing 500 cc. of antimony and potassium tartrate with 500 cc. of 1.0 Nsulfathiazole sodium. In the course of a minute the complex is formed.Another method of making this white antimony sulfathiazole complex is toadd 250 grams of sulfathiazole to cc. of 1.0 N antimony and potassiumtartrate. To aid in the solution of the sulfathiazole 250 cc. ofconcentrated hydrochloric acid is added. Upon standing the complex isformed.

Example 38 Antimony sulfaguanidine complex-232 grams of sulfaguanidineare added to 10 cc. of 1.0 N antimony and potassium tartrate. From 100to 300 cc. of concentrated hydrochloric acid are added to completelydissolve the sulfaguam'dine. Upon standing the complex separates out ofthe solution.

Example 39 Antimony sulfadz'azine complex.This complex is formed byadding 500 cc. of 1.0 N antimony and potassium tartrate to 500 cc. of1.0 N sulfadiazine. Another method is to dissolve 250 grams ofsulfadiazine in 1000 cc. of antimony and potassium tartrate containing450 cc. of concentrated hydrochloric acid. Upon standing over night thecomplex precipitates out.

Example 40 Antimony suljapyridine complex.This complex is formed byadding 500 cc. of 1.0 N antimony and potassium tartrate to 500 cc. of1.0 N sulfapyridine sodium. More rapid and complete precipitation isbrought about by cooling the solution once the reaction has taken place.Another method is to dissolve 249 grams of sulfapyridine in 1000 cc. of1.0 N antimony and potassium tartrate containing 300 cc. of concentratedhydrochloric acid. Upon standing over night or cooling the crystallinecomplex is formed.

Example 41 Antimony sulfanilamide complex.This complex is formed uponmixing 500 cc. of 1.0 N antimony and potassium tartrate with 500 cc. of1.0 N sulfanilamide sodium. Another way of making this complex is todissolve 172 grams of sulfanilamide in 1000 cc. of 1.0 N antimony andpotassium tartrate containing 300 cc. of concentrated hydrochloric acid.From the clear solution a precipitate is formed upon standing.

While I have set forth in detail the preferred compounds and methods ofprocedure, these are capable of variation and modification withoutdeparting from the spirit of the invention. I therefore do not wish tobe limited to the precise details disclosed, but desire to avail myselfof such variations and modifications as fall within the scope of theappended claim.

I claim:

As a new chemical compound of therapeutic value an arsenic sulfathiazolecomplex in which the arsenic has at least one bond with the N1 atom of asulfathiazole structure, and at least one chelate bond with one of thestrongly polar atoms of the thiazole ring.

IBERT MELLAN.

(References on following page) 9 10 REFERENCES CITED OTHER REFERENCESThe following references are of record in the Scudi: Jour. Ind. &Eng.Chem. (Analytical EdJ. file O t Patent: vol. 10, No. 6 (June 15, 1938).

UNITED STATES PATENTS 5 Crossley et aL: Jour. Am. Chem. Soc. (Oct.

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Number Country Date 849,504 France Nov. 25, 1939 111,230 Australia Aug.22, 1940

